Rak Aleksandra, Canale Vittorio, Marciniec Krzysztof, Żmudzki Paweł, Kotańska Magdalena, Knutelska Joanna, Siwek Agata, Stachowicz Gabriela, Bednarski Marek, Nowiński Leszek, Zygmunt Małgorzata, Zajdel Paweł, Sapa Jacek
Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Bioorg Med Chem. 2016 Nov 1;24(21):5582-5591. doi: 10.1016/j.bmc.2016.09.017. Epub 2016 Sep 10.
A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α-adrenoceptor antagonists with uroselective profile. Biological evaluation for α- and α-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α-adrenoceptor (K=34-348nM) and moderate selectivity over α-receptor subtype. Compounds with highest affinity and selectivity for α-adrenoceptor were evaluated in vitro for their intrinsic activity toward α- and α-adrenoceptor subtypes. All compounds behaved as antagonists at both α-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.
合成了一系列（芳氧基）乙基吡咯烷和哌啶的芳基磺酰胺衍生物，以开发具有尿选择性的新型α-肾上腺素能受体拮抗剂。对α-和α-肾上腺素能受体的生物学评价表明，受试化合物13-37对α-肾上腺素能受体表现出高至中等亲和力（K = 34-348 nM），对α-受体亚型具有中等选择性。对α-肾上腺素能受体具有最高亲和力和选择性的化合物在体外评估其对α-和α-肾上腺素能受体亚型的内在活性。所有化合物在两种α-肾上腺素能受体亚型上均表现为拮抗剂，对α-亚型表现出2至6倍的功能偏好。其中，N-{1-[2-(2-甲氧基苯氧基)乙基]哌啶-4-基}异喹啉-4-磺酰胺（25）和3-氯-2-氟-N-{[1-(2-(2-异丙氧基苯氧基)乙基)哌啶-4-基]甲基}苯磺酰胺（34）对α-肾上腺素能受体表现出最高偏好。最后，与坦索罗辛（1-2mg/kg，静脉注射）相比，化合物25和34（2-5mg/kg，静脉注射）在正常血压麻醉大鼠中未显著降低收缩压和舒张压，以确定它们对血压的影响。
